4f3i

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==Crystal structure of the first bromodomain of human BRD4 in complex with MS417 inhibitor==
==Crystal structure of the first bromodomain of human BRD4 in complex with MS417 inhibitor==
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<StructureSection load='4f3i' size='340' side='right' caption='[[4f3i]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
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<StructureSection load='4f3i' size='340' side='right'caption='[[4f3i]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4f3i]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F3I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F3I FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4f3i]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F3I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F3I FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0S6:METHYL+[(6S)-4-(4-CHLOROPHENYL)-2,3,9-TRIMETHYL-6H-THIENO[3,2-F][1,2,4]TRIAZOLO[4,3-A][1,4]DIAZEPIN-6-YL]ACETATE'>0S6</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.4&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0S6:METHYL+[(6S)-4-(4-CHLOROPHENYL)-2,3,9-TRIMETHYL-6H-THIENO[3,2-F][1,2,4]TRIAZOLO[4,3-A][1,4]DIAZEPIN-6-YL]ACETATE'>0S6</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4f3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f3i OCA], [http://pdbe.org/4f3i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4f3i RCSB], [http://www.ebi.ac.uk/pdbsum/4f3i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4f3i ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4f3i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f3i OCA], [https://pdbe.org/4f3i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f3i RCSB], [https://www.ebi.ac.uk/pdbsum/4f3i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f3i ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
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[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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NF-kappaB-mediated inflammation is the major pathology in chronic kidney diseases, including HIV-associated nephropathy (HIVAN) that ultimately progresses to end stage renal disease. HIV infection in the kidney induces NF-kappaB activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-kappaB transcriptional activity by small molecule blocking NF-kappaB binding to the transcriptional cofactor BRD4, which is required for the assembly of the productive transcriptional complex comprising positive transcription elongation factor b and RNA polymerase II. We showed that our BET (Bromodomain and Extra-Terminal domain)-specific bromodomain inhibitor MS417, designed to block BRD4 binding to the acetylated NF-kappaB, effectively attenuates NF-kappaB transcriptional activation of proinflammatory genes in kidney cells treated with TNFalpha or infected by HIV. MS417 ameliorates inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIVAN. Our study suggests that BET bromodomain inhibition, targeting at the proinflammatory activity of NF-kappaB, represents a new therapeutic approach for treating NF-kappaB-mediated inflammation and kidney injury in HIVAN.
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Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition.,Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Nevarro G, Moshkina N, Joshua J, Chuang PY, Ohlmeyer M, He JC, Zhou MM J Biol Chem. 2012 Aug 17;287(34):28840-51. Epub 2012 May 29. PMID:22645123<ref>PMID:22645123</ref>
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==See Also==
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*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4f3i" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Joshua, J]]
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[[Category: Large Structures]]
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[[Category: Plotnikov, A N]]
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[[Category: Joshua J]]
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[[Category: Zhou, M M]]
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[[Category: Plotnikov AN]]
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[[Category: Acetyl-lysine binding]]
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[[Category: Zhou M-M]]
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[[Category: Nucleus]]
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[[Category: Protein-inhibitor complex]]
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[[Category: Signaling protein-inhibitor complex]]
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Current revision

Crystal structure of the first bromodomain of human BRD4 in complex with MS417 inhibitor

PDB ID 4f3i

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